Division of Neuromuscular MedicineDavee Department of Neurology and Clinical Neurosciences and the Department of Cell and Molecular BiologyNorthwestern University Feinberg School of MedicineChicago, Illinois

Summary

Clinical characteristics.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper motor neurons (UMN) and lower motor neurons (LMN). UMN signs include hyperreflexia, extensor plantar response, increased muscle tone, and weakness in a topographic representation. LMN signs include weakness, muscle wasting, hyporeflexia, muscle cramps, and fasciculations. Initial presentation varies. Affected individuals typically present with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and labile affect, but not necessarily mood. Regardless of initial symptoms, atrophy and weakness eventually affect other muscles. The mean age of onset is 56 years in individuals with no known family history and 46 years in individuals with more than one affected family member (familial ALS or FALS). Average disease duration is about three years, but it can vary significantly. Death usually results from compromise of the respiratory muscles.

Diagnosis/testing.

The diagnosis of ALS is based on clinical features, electrodiagnostic testing, and exclusion of other health conditions with related symptoms. Molecular genetic testing plays a prominent role in diagnosis of the genetic subtype and genetic counseling.

Management.

Treatment of manifestations: Treatment is palliative. Individuals with ALS may benefit from care by a multidisciplinary team that includes a neurologist, specially trained nurses, pulmonologist, speech therapist, physical therapist, occupational therapist, respiratory therapist, nutritionist, psychologist, social worker, and genetics professional. Riluzole is the only currently FDA-approved drug for treatment of ALS. Oral secretions in those with bulbar symptoms can be reduced with tricylic antidepressants and other anticholinergic agents. Pseudobulbar affect can be managed with antidepressants. Swallowing difficulties can be alleviated by thickening liquids and pureeing solid food and, eventually, by use of a gastrostomy tube to help maintain caloric intake and hydration. Medications such as baclofen and benzodiazepines can help relieve spasticity and muscle cramps. Alphabet boards and computer-assisted devices can aid communication. Other assistive devices such as walkers, wheelchairs, bathroom modifications, hospital beds, and Hoyer lifts can aid in activities of daily life. Ventilatory assistance may include BIPAP and/or mechanical ventilation. Hospice care in terminal stages is beneficial.

Definition

Clinical Manifestations of ALS

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease involving both upper motor neurons (UMNs) and lower motor neurons (LMNs). Upper motor neurons, located in the motor cortex of the frontal lobe, send their axons through the great corticofugal tracts to the brain stem (corticobulbar neurons) and the spinal cord (corticospinal neurons) to influence patterned activity of the lower motor neurons (LMS). Additional UMN influences on the LMN are carried over descending pathways of the brain stem. UMN signs in ALS include hyperreflexia, extensor plantar response, and increased muscle tone. Lower motor neurons, located in the brain stem and spinal cord, innervate striated muscle. LMN signs in ALS include weakness, muscle wasting (atrophy), hyporeflexia, muscle cramps, and fasciculations.

Clinical characteristics. Symptoms present in early disease may vary. Affected individuals most often present with either asymmetric focal weakness of the extremities (stumbling or poor handgrip) or bulbar findings (dysarthria, dysphagia). Other findings may include muscle fasciculations, muscle cramps, and lability of affect, but not necessarily mood. A diagnostic feature of ALS, typically not seen in other disorders, is the presence of hyperreflexia in segmental regions of muscle atrophy, unaccompanied by sensory disturbance.

At presentation, limb involvement occurs more often than bulbar involvement. Onset in the lower extremities is most common for familial ALS [Mulder et al 1986, Siddique 1991]. Various subtypes of ALS may be identified:

Progressive muscular atrophy in which only lower motor neurons are involved; and

UMN-predominant ALS.

Regardless of initial symptoms, atrophy and weakness eventually spread to affect other muscles.

Oculomotor neurons are generally resistant to degeneration in ALS, but may be affected in individuals with a long disease course, especially when life span is extended by ventilatory support. Once all muscles of communication and expression are paralyzed, the individual is "locked in." In some instances, eye movements remain intact, allowing communication by way of special devices.

Death usually results from compromise of the respiratory muscles.

Frontotemporal involvement. Frontotemporal dementia (FTD) is a profound alteration in personality and social conduct characterized by loss of volition and insight, social disinhibition, and distractibility, with preservation of memory function [Neary et al 1998]. Common features include cognitive deficits in attention, abstraction, planning, and problem solving with preservation of perception and spatial functions. Language may be preferentially involved in individuals with progressive aphasia.

About 5% of individuals with ALS, regardless of family history, have FTD, which meets clinical criteria described by Neary et al [1998]. In families with dominantly inherited ALS/FTD, one member may have either FTD or ALS or both conditions [Hosler et al 2000].

From 30% to 50% of individuals with ALS have executive function impairment but do not meet the Neary criteria for dementia [Portet et al 2000, Lomen-Hoerth et al 2003]. In contrast to individuals with FTD, individuals with ALS may have more subtle deficits in executive function that may be missed with routine mental status examination. Formal neuropsychological testing can identify subtle alterations which may be masked by socially favorable traits such as empathy and optimism. These favorable traits have been known to specialists dealing with ALS and lead to considerable bonding between health care givers and persons with ALS. Affected individuals are also generally well-liked by the family, as social connections are maintained and their 'positive' attitudes are appreciated.

Individuals with ALS without frontotemporal dementia who exhibit executive dysfunction including deficits in verbal and nonverbal fluency and concept formation may do so early in the disease course. Executive dysfunction is seen more often in those with bulbar onset of disease [Schreiber et al 2005].

Additionally, white matter structural abnormalities may be present in the frontal and temporal lobes of individuals with ALS who do not demonstrate evidence of cognitive change [Abrahams et al 2005].

Conversely, Lomen-Hoerth et al [2002] report that clinical examination of 36 individuals with FTD and no family history of ALS or FTD revealed definite ALS in six and signs suggestive of ALS in another third.

Course. Sporadic ALS (SALS), or ALS in an individual with no family history of ALS, can be distinguished from familial ALS (FALS), or ALS in an individual from a family with at least one other blood relative affected with ALS. They are clinically similar. However, the mean age of onset in SALS is 56 years [Testa et al 2004], while the mean age of onset in FALS is approximately 46 years [Juneja et al 1997]. In general, individuals younger than age 55 years at onset of symptoms survive longer, regardless of gender [Magnus et al 2002]. Individuals who are diagnosed with ALS after age 80 years survive 1.7 years less than those with onset before age 80 [Forbes et al 2004]. Although respiratory function declines faster in ALS with bulbar onset, overall muscle weakness declines more slowly [Magnus et al 2002]. Progression in FALS may be significantly shorter or longer than in SALS and may be correlated with particular pathogenic variants [Cudkowicz et al 1997, Juneja et al 1997].

Other. In SALS males are more likely to be affected than females at a rate of 1.3:1.

Penetrance of familial ALS is age and mutation dependent. Fifty percent of individuals with an SOD1 pathogenic allelic variant are symptomatic by age 46 years; 90% are symptomatic by age 70 years [Siddique 1991]. However, these percentages may be an overestimate because of ascertainment bias in families with high penetrance.

From 50% to 70% of individuals with one of two common FUS pathogenic variants are symptomatic by age 51 years, and more than 90% are symptomatic by age 71 years [Blair et al 2010].

Establishing the Diagnosis of ALS

The diagnosis of ALS requires characteristic clinical features and findings on electrodiagnostic testing, as well as exclusion of other health conditions with related symptoms (see Differential Diagnosis of ALS).

Clinical features. The Escorial criteria [Brooks et al 2000] were developed to standardize diagnosis of ALS for research studies. While not all clinicians employ such stringent criteria, these criteria are increasingly used in everyday practice. They include:

Progressive spread of symptoms or signs within a region or to other regions, as determined by history or examination

Together with the absence of:

Electrophysiologic or pathologic evidence of other disease processes that could explain the signs of LMN and/or UMN degeneration AND

Neuroimaging evidence of other disease processes that might explain the observed clinical and electrophysiologic signs.

Clinical evidence of UMN and LMN signs in four regions of the central nervous system (i.e., brain stem, cervical, thoracic, or lumbosacral spinal cord) can be obtained through careful history and physical and neurologic examinations.

The clinical diagnosis of ALS, without pathologic confirmation, may be categorized into various levels of certainty by clinical and laboratory assessment based on the Escorial criteria [Brooks et al 2000]:

Clinically definite ALS. The presence of UMN and LMN signs in three regions

Clinically definite familial, laboratory-supported ALS. Progressive upper and/or lower motor neuron signs in at least a single region (in the absence of another cause for the abnormal neurologic signs) in an individual with an identified ALS-causing variant

Clinically probable ALS. The presence of UMN signs and LMN signs in at least two regions with some UMN signs necessarily rostral to (i.e., above) the LMN signs

Clinically probable, laboratory-supported ALS. Clinical signs of UMN and LMN dysfunction are in only one region, or UMN signs alone present in one region, and LMN signs defined by electromyogram (EMG) criteria present in at least two limbs

Clinically possible ALS. Clinical signs of UMN and LMN dysfunction found together in only one region, UMN signs found alone in two or more regions or LMN signs found rostral to UMN signs when the diagnosis of clinically probable, laboratory-supported ALS cannot be established.

Pathology. A definitive diagnosis of ALS can be made based on brain stem and spinal cord pathology. Pathologic changes:

Degeneration and loss of the motor neurons in the anterior horns and in the motor nuclei of cranial nerves VII, X, and XI and most commonly the hypoglossal nucleus

Axonal loss with decreased myelin staining in the lateral and anterior corticospinal tracts. Degeneration of the corticobulbar and corticospinal tract is detected at the level of the internal capsule and cerebral peduncles in the midbrain.

Some individuals show mild degeneration of the mid-zone of the posterior sensory tracts, although sensory loss is usually not apparent during life.

Loss of Betz cells in the motor cortex has been documented but can be missed because of the paucity of Betz cells.

Differential Diagnosis of ALS

Other hereditary and acquired conditions to be considered when establishing the diagnosis of ALS are discussed below [Traynor et al 2000].

Hereditary disorders include the following:

Spinal and bulbar muscular atrophy (SBMA, Kennedy disease) is an X-linked disorder, typically occurring in males only, characterized by proximal muscle weakness, muscle atrophy, and fasciculations. Affected males may have gynecomastia, testicular atrophy, and reduced fertility as a result of androgen insensitivity. SBMA can be distinguished clinically from non-familial ALS by the lack of upper motor neuron involvement, slow course, gynecomastia, and sensory involvement. Molecular genetic testing of the androgen receptor gene (AR) is diagnostic.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by progressive degeneration and loss of anterior horn cells in the spinal cord and in some brain stem nuclei, resulting in proximal-greater-than-distal symmetric muscle weakness and atrophy (LMN involvement only). The onset of weakness ranges from before birth to adulthood. Molecular genetic testing of SMN identifies most individuals with spinal muscular atrophy caused by mutation of SMN.

ALS8 (also known as SMAIV or Finkel type SMA) could be considered in the context of normal SMN test results in an individual with adult-onset LMN disease with some UMN involvement. ALS8 is caused by mutation of VAPB and inherited in an autosomal dominant manner [Nishimura et al 2004].

Primary lateral sclerosis (PLS) refers to the presence of slowly progressive, uncomplicated signs of upper motor neuron disease in persons in whom all other known causes of spasticity have been eliminated. Controversy exists as to whether PLS is a separate disorder or a subtype of ALS. Upper motor neuron-predominant ALS has little, often late, involvement of LMNs. Adult-onset PLS is a sporadic disorder, while at least a portion of juvenile-onset PLS is a recessive disorder. It may present as a progressive ascending paralysis first noted in infancy [Strong & Gordon 2005]. Pathogenic variants in at least one gene (ALS2) are associated with both ALS and PLS (see Table 2).

Hereditary spastic paraplegia (HSP) is characterized by insidiously progressive lower extremity weakness and spasticity. HSP is classified as "uncomplicated" if neurologic impairment is limited to progressive lower extremity spastic weakness, hypertonic urinary bladder, mild diminution of lower extremity vibration sensation, and, occasionally, joint position sensation. "Complicated" HSP is accompanied by other system involvement or other neurologic findings including seizures, dementia, amyotrophy, extrapyramidal disturbance, or peripheral neuropathy. Nonsyndromic or pure HSP does not reduce life span. HSP is genetically heterogeneous and can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner.

Hexosaminadase A deficiency results in a group of neurodegenerative disorders caused by intralysosomal storage of the specific glycosphingolipid GM2 ganglioside. The juvenile, chronic, and adult-onset variants of hexosaminidase A deficiency are slowly progressive and have variable neurologic findings, including progressive dystonia, spinocerebellar degeneration, motor neuron disease, and, in some individuals with adult-onset disease, a bipolar form of psychosis.

Cervical spondylosis with cervical stenosis causing UMN signs in the legs and LMN signs in the arms should be considered as a differential diagnosis. Because cervical spondylosis is common, it is often identified in individuals who also have ALS. Electromyogram (EMG) and nerve conduction velocity (NCV) testing are performed to establish clinical evidence and extent of LMN disease.

To evaluate for other health conditions with related symptoms, the following may be performed:

Prevalence of ALS

The number of individuals newly diagnosed with ALS each year is 1-3:100,000.

The prevalence of individuals with ALS is roughly 4-8:100,000 [Traynor et al 1999] and is similar to the number of newly diagnosed individuals each year because people generally live only two to five years after the diagnosis of ALS is established.

The mean age of diagnosis in sporadic ALS is 56 years; individuals age 80 years and older have a standardized incidence of 10.2:100,000 in men and 6.1:100,000 in women [Forbes et al 2004].

Ethnic presentation of ALS worldwide is equal with the exception of the South Pacific (Guam) where the incidence of an ALS/parkinsonism/dementia complex is higher [Plato et al 2002, Waring et al 2004]. Although recent studies suggest a lower incidence in African populations, those need to be verified by population-based prospective studies.

Causes

Environmental (Acquired) Causes of ALS

Over the years a multitude of environmental exposures have been proposed as possible contributors to the cause of ALS, including mercury, manganese, and products used in farming (fertilizers, insecticides, herbicides), in addition to physical and dietary factors [Wicklund 2005].

Environmental exposures have been proposed as the explanation for an increased incidence of ALS in Gulf War veterans [Haley 2003, Horner et al 2003]. Further investigation is ongoing, and a registry has been developed for veterans with ALS [Kasarkis et al 2004]. Of note, veterans with a diagnosis of ALS are entitled to Veterans' Administration healthcare and disability benefits.

Heritable Causes

An estimated 10% of individuals with ALS have at least one other affected family member and are said to have familial ALS (FALS).

Orrell et al [1997] reported a range of duration of 2.5 to 20 years in individuals with the p.Ile113Thr variant and of two to 12 years in individuals with the p.Gly93Arg variant.

The p.Ala4Val pathogenic variant, present in approximately 50% of all North American families with identifiable SOD1 variants, is consistently associated with a rapid average disease course of one year [Juneja et al 1997].

On the opposite end of the spectrum are pathogenic variants that confer a significantly longer mean duration of at least 17 years, including p.Gly37Arg, p.Gly41Asp, p.His46Arg, and p.Glu100Lys [Cudkowicz et al 1997; Juneja et al 1997; Siddique & Brooks, unpublished observation].

Clinical presentation can occasionally be correlated with SOD1 pathogenic variants. Symptomatic persons with p.Ala4Val and p.Val148 variants often have few UMN findings, which is the basis for the Escorial criterion that LMN findings in a person with an SOD1 pathogenic variant are sufficient to establish the diagnosis of ALS [Cudkowicz et al 1998].

Persons with the p.Asp90Ala variant can present with ataxia, which can confuse the diagnosis initially.

The p.Asp90Ala variant is noteworthy for its ethnic distribution and inheritance: individuals heterozygous for p.Asp90Ala from northern Sweden and Finland remain unaffected, while homozygotes develop ALS [Själander et al 1995]. Symptomatic heterozygotes have been identified in other populations, although they often have a slowly progressive course [Al-Chalabi et al 1998].

One family was identified as possibly having autosomal recessive ALS with a characteristic phenotype of lower limb onset, slow disease duration, and age of onset between 30 and 45 years. Affected individuals of this family are compound heterozygous for a p.Asp90Ala variant and a p.Asp96Asn variant; those family members who are heterozygous for one pathogenic variant only did not manifest the disease [Hand et al 2001].

The cDNA and protein reference sequences for SOD1 are NM_000454.4 and NP_000445.1, respectively. By SOD1 convention, numbering does not begin with the initiating methionine codon, but rather the second codon for alanine. The amino acid numbering for pathogenic variants in this GeneReview follow this convention.

ALS3. In one large pedigree, presentation typical of ALS began in the legs for the majority of individuals; onset was age 45 years and duration was five years. No atypical features (e.g., pain, dementia, sensory loss, or cerebellar degeneration) were observed [Hand et al 2002].

ALS4 (juvenile-onset motor neuron disease with dominant inheritance and no bulbar involvement). ALS4 is associated with slowly progressive distal muscle weakness and atrophy with UMN signs, normal sensation, and absence of bulbar involvement [Rabin et al 1999]. De Jonghe et al [2002] identified three additional families of Belgian, Austrian, and English ancestry. Onset is in adolescence. The duration can be long, with some persons living a full life span. ALS4 is associated with mutation of SETX encoding the protein senataxin, which constitutes a DNA/RNA helicase domain with a possible role in RNA processing [Chen et al 2004]. Pathogenic variants in SETX have also been identified in individuals with ataxia and oculomotor apraxia type 2 (AOA2).

ALS6. Pathogenic variants in FUS (also known as TLS) have recently been identified in approximately 4% of SOD1-negative FALS cases, although screening of large FALS cohorts is necessary to establish exact prevalence. Kwiatkowski et al [2009] identified homozygous p.His517Gln (c.1551C>G) missense variants in four individuals with ALS from a family of Cape Verdean origin. Their disease was characterized by proximal upper extremity weakness spreading to the lower extremities but not the bulbar region. The proband’s maternal grandparents were first cousins. Additional FUS screening revealed 13 FUS/TLS pathogenic variants in 17 families with FALS, whereas no FUS/TLS pathogenic variants were found in 293 individuals with SALS. The most common variants were p.Arg521Cys and p.Arg521Gly, each identified in three families.

Further studies and analysis of pathology tissue from a p.Arg521Gly-positive individual showed diffuse ubiquitin positivity indicating cytoplasmic retention and aggregation of the mutant protein. FUS/TLS encodes a nucleoprotein that functions in DNA and RNA metabolism and has been implicated with tumorigenesis [Kwiatkowski et al 2009].

Independently Vance et al [2009] identified the p.Arg521Cys pathogenic variant in six members of a British kindred previously linked to chromosome 16. The same variant was identified in four additional individuals in a cohort of 197 FALS index cases. Moreover, two novel missense variants were identified in eight families.

Consistent with the observation of Kwiatkowski et al [2009], neuropathology on three individuals positive for FUS/TLS variants showed FUS-immunoreactive cytoplasmic inclusions as well as predominant lower motor neuron disease. Clinical information on 20 individuals with ALS6 revealed even gender distribution, average age of onset of 44.5 years, and cervical onset in ten, lumbar onset in five, and bulbar onset in three. No affected individuals developed cognitive deficits.

ALS8. Known as SMAIV, or Finkel type SMA, ALS8 is characterized by primarily LMN findings, with UMN findings in some families. ALS8 is caused by mutation of VAPB, which encodes a protein that acts during ER-Golgi transport and secretion [Nishimura et al 2004]. The same p.Pro56Ser pathogenic variant was identified in one large family and six additional kindreds, all of whom have different courses (ALS8, late-onset SMA, and ALS with rapid progression). Haplotype analysis revealed that the p.Pro56Ser mutation is a founder variant in individuals of Portuguese/Brazilian and African/Brazilian ancestry, a finding consistent with the Portuguese colonization of Brazil [Nishimura et al 2004].

ALS9. ALS9 has been reported in a small number of French, Italian, North American, and northern European individuals with both sporadic and familial ALS [Greenway et al 2006, Wu et al 2007, Gellera et al 2008, Paubel et al 2008]. Affected individuals were reported to have typical ALS although a higher-than-expected proportion (60%) of individuals in the European cohort with ANG pathogenic variants had bulbar-onset disease.

The NP_001136.1:p.Arg145His (or Arg121His in the mature protein; also known as R121H) variant was associated with rapid progression in a French individual.

The NP_001136.1:p.Lys41Ile (or Lys17Ile in the mature protein; also known as K17I) allelic variant (also found in healthy individuals, see following) was identified in a large Dutch kindred with FALS characterized by limb onset lower motor neuron-predominant disease with rapid to average progression. One affected individual had a five-year history of Parkinson disease prior to onset of ALS and symptoms suggestive of FTD.

The pathogenesis of ANG variants remains to be established as the NP_001136.1:p.Ile70Val (or Ile46Val in the mature protein) and p.Lys41Ile variants were also found in healthy individuals [Greenway et al 2006, Gellera et al 2008]. While variants in ANG have not been robustly linked with ALS as a Mendelian disorder, they most likely constitute a risk factor in certain populations.

Spinal onset was reported in 77% of individuals with TARDBP pathogenic variants and lower motor neuron-predominant disease was seen in 39% [Kühnlein et al 2008]. FTD and/or cognitive impairments have not been reported in individuals with TARDBP pathogenic variants.

TARDBP encodes TDP-43, an RNA- and DNA-binding protein involved in regulation of gene expression and splicing. Interestingly, ubiquitinated TDP-43 inclusion bodies are found at autopsy in SOD1-negative FALS [Van Deerlin et al 2008] as well as in frontotemporal lobar degeneration (FTLD), further suggesting a clinical overlap between ALS and FTD. TDP-43 inclusions have been noted more widely; for example, they have been described in Alzheimer disease and other neurodegenerative disorders.

ALS11 (FIG4-related ALS). ALS11 was reported in five unrelated individuals of European descent diagnosed with probable or definite ALS, with two having a family history of the disorder [Chow et al 2009]. All had adult onset disease and showed prominent corticospinal tract findings. Nerve conduction velocity studies were normal; EMG studies showed some denervation [Chow et al 2009].

The five individuals were heterozygous for either a missense (1 person), splice site (2), or truncating (2) variant in FIG4; all five variants resulted in complete or highly significant loss of protein function [Chow et al 2009].

C9FTD/ALS(C9orf72-related ALS). Individuals and family members with this syndrome have an FTD syndrome of behavioral change with relatively intact memory associated with signs of motor neuron disease. The associated FTD may be initially diagnosed as Alzheimer disease, mild cognitive impairment, or dementia with Lewy bodies [Murray et al 2011].

An expansion of a non-coding GGGGCC hexanucleotide repeat in C9orf72 was strongly associated with disease in a large FTD/ALS kindred. Further analysis of extended clinical series found the C9orf72 repeat expansion to be the most common genetic abnormality in both familial FTD (11.7%) and familial ALS (23.5%) [DeJesus-Hernandez et al 2011]. The repeat expansion leads to the loss of one alternatively spliced C9orf72 transcript and to formation of nuclear RNA foci, suggesting multiple disease mechanisms [DeJesus-Hernandez et al 2011].

In one study, all individuals with the C9orf72 repeat expansion presented with classic ALS with the exception of one person diagnosed with progressive muscular atrophy without upper motor neuron signs. Three individuals (18.8%) were diagnosed with a combined ALS/FTD phenotype. In the individuals with ALS with expanded repeats, 11 (68.8%) of 16 reported relatives with FTD or dementia, compared to only 61 (28.6%) of 213 individuals with ALS without repeat expansions [DeJesus-Hernandez et al 2011]. On autopsy, affected individuals exhibited TDP-43 based pathology [DeJesus-Hernandez et al 2011].

Wilhelmsen et al [2004] reported a family with ALS/FTD from San Francisco with α-synuclein and 4R/0N tau pathology linked to chromosome 17q. Clinical features include FTD, variable extrapyramidal symptoms, and prominent motor neuron disease. Family members reported frontal and anterior lobe dysfunction decades prior to onset of FTD or ALS. Three affected family members succumbed to ALS in their 50s or 60s within a few years of diagnosis. One presented with PSP-like syndrome in his 80s. Affected family members tested negative for pathogenic variants in MAPT, encoding the protein tau.

Pathologic findings include distinctive tau and α-synuclein inclusions. The insoluble tau protein inclusions consist predominantly of the 4R/0N isoform located almost exclusively in affected regions of the brain.

ALS2. Alsin-related disorders (ALS2-related disorders) involve retrograde degeneration of the upper motor neurons of the pyramidal tracts, which at onset appears as infantile ascending spastic paralysis (IAHSP); but all reported cases eventually end up as primary lateral sclerosis (JPLS). Other families also have lower motor neuron involvement resulting in a picture of upper motor neuron-predominant ALS.

ALS2-related disorders are characterized by onset during childhood (mean age at onset 6.5 years), spasticity of facial muscles, uncontrolled laughter, spastic dysarthria, spastic gait, inconstant moderate muscle atrophy, bladder dysfunction, and sensory disturbances; some individuals are bedridden by age 12 to 50 years.

ALS2 makes two transcripts of the protein by alternate splicing of a long form (resulting in juvenile-onset PLS) and a short form (resulting in juvenile-onset ALS) [Yang et al 2001]. Pathogenic variants in ALS2 have not been identified in individuals with adult-onset ALS [Hand et al 2003].

ALS5. Families with ALS5 from Tunisia, South Asia, and Germany have onset between ages eight and 18 years, with both UMN and LMN signs, fasciculations and atrophy of the tongue, and, occasionally, mild intellectual disability [Hentati et al 1998].

ALS12. ALS12 results from homozygous or heterozygous mutation of OPTN, encoding optineurin and mapping to chromosome 10p15-p14. Inheritance is autosomal recessive or autosomal dominant. Individuals with ALS12 were of Japanese descent and the result of consanguineous marriages. Age of onset ranged from the third to sixth decade. Most showed slow progression and extended disease duration before succumbing to respiratory failure [Maruyama et al 2010].

Optineurin has been shown to be involved in the pathogenesis of sporadic ALS and non-SOD1familial ALS, indicating that these forms of ALS share a pathway that is distinct from that of SOD1-linked ALS [Deng et al 2011b].

In additional families, neither mutation of ALS2 or OPTN nor linkage to 15q has been identified.

SPG20(Troyer syndrome) is characterized by spastic paraparesis with dysarthria, distal amyotrophy, mild developmental delay, and short stature. Most affected children have delay in reaching the early developmental milestones (walking and talking), followed by slow deterioration in both gait and speech. Emotional lability and affective disorders such as inappropriate euphoria and/or crying are common. Mild cerebellar signs are common. The most severely affected individuals have choreoathetosis. It is caused by mutation of SPG20, encoding the protein spartin, which may be involved in endosomal trafficking.

Ubiquilin-2 pathology was reported in the spinal cords of individuals with ALS and in the brains of individuals with ALS/dementia with or without UBQLN2 pathogenic variants [Deng et al 2011a].

Ubiquilin-2 is a member of the ubiquilin family, which regulates the degradation of ubiquitinated proteins; functional analyses showed that mutation of UBQLN2 leads to an impairment of protein degradation [Deng et al 2011a]. These findings link abnormalities in ubiquilin-2 to defects in the protein degradation pathway, abnormal protein aggregation, and neurodegeneration, indicating a common pathogenic mechanism that can be exploited for therapeutic intervention [Deng et al 2011a].

Other. X-chromosomelinkage was established in five families with adult-onset FALS in which no male-to-male transmission was evident. Clinically, these families had classic UMN and LMN involvement, with UMN signs typically preceding LMN signs. Male family members also had much earlier onset than females, often by age 20 years [Hong et al 1998].

Sporadic ALS

About 90% of ALS occurs in individuals with no family history of ALS; such individuals are said to have sporadic ALS (SALS). Note: True sporadic ALS needs to be distinguished from inherited ALS that occurs in simplex cases (i.e., affected individuals who have no family history of the disorder). For example, because of the decreased penetrance of some SOD1 pathogenic variants, an individual with an SOD1 pathogenic variant may sometimes be the only known affected family member (i.e., a simplex case), and thus be considered (incorrectly) a sporadic case.

Recent reports indicate a role of TARDBP variants in what appeared to be sporadic ALS. Additional research is required to establish reduced penetrance, variable expressivity, and de novomutation rate of both ANG and TARDBP pathogenic variants in SALS. These reports do not describe the extent of family history obtained to clearly establish that such individuals are simplex cases.

The etiology of sporadic ALS is unknown but is thought to be multifactorial. A combination of oxidative stress, glutamate excitotoxicity, mitochondrial dysfunction, inflammation, and apoptosis has repeatedly been proposed [Cleveland & Rothstein 2001] but not validated:

Mutation of the gene encoding vascular endothelial growth factor (VEGF) has also been proposed as playing a role in modifying ALS [Lambrechts et al 2003]. Although VEGF and related proteins probably have a biologic role in ALS, it is unlikely an etiologic role [Chen et al 2006].

Pathogenic variants in APOE, in particular the E*2 allele, may protect against the early onset of ALS [Li et al 2004].

Single-nucleotide polymorphisms (SNPs) in the paraoxonase gene cluster (PON) on chromosome 7q have been associated with sporadic ALS [Saeed et al 2006] in ethnically diverse populations. Serum paraoxonase is associated with high density lipoprotein (HDL), and polymorphisms in PON are associated with increased risk of coronary heart disease. PON enzymes are involved in the metabolism of intrinsic oxidized lipoid products and xenobiotics such as insecticides and nerve gas agents, as well as statin drugs.

Evaluation Strategy

Once the diagnosis of ALS has been established in an individual, the following approach can be used to determine the specific subtype of ALS to aid in discussions of prognosis and genetic counseling. Establishing the specific subtype of ALS in a given individual usually involves obtaining family history and performing molecular genetic testing.

Family history. A three-generation family history with attention to other relatives with neurologic signs and symptoms should be obtained. Documentation of relevant findings in relatives can be accomplished either through direct examination of those individuals or by review of their medical records including the results of molecular genetic testing, neuroimaging studies, and autopsy examinations.

Molecular genetic testing. Molecular genetic testing should be accompanied by formal genetic counseling and may include the following:

SOD1 testing is appropriate in any individual with ALS who has another affected family member or an incomplete family history, including the early death of a close relative from any cause. Approximately 20% of individuals with FALS have ALS1 with an identified pathogenic variant in SOD1. Interpretation of the significance of an SOD1 variant regarding disease severity and progression depends on the specific variant identified because of wide variability in genotype/phenotype correlations. Failure to detect an SOD1 variant does not rule out FALS.

Up to 3% of individuals with ALS with no family history of ALS have SOD1 variants. Because data on penetrance of many variants are limited, establishing the risk to other family members of developing clinical symptoms can be difficult.

Multi-gene testing. Consider using a multi-gene ALS panel that includes a number of other genes associated with ALS.

Note: Multi-gene panels vary by methods used and genes included; thus, the ability of a panel to detect a causative variant or variants in any given individual with ALS also varies.

Genetic Counseling

Genetic counseling is the process of
providing individuals and families with information on the nature, inheritance,
and implications of genetic disorders to help them make informed medical and
personal decisions. The following section deals with genetic risk assessment and
the use of family history and genetic testing to clarify genetic status for
family members. This section is not meant to address all personal, cultural, or
ethical issues that individuals may face or to substitute for consultation with
a genetics professional. —ED.

Parents of a proband with an apparent de novo pathogenic variant can be offered molecular genetic testing; however, molecular genetic testing should be performed in the context of formal genetic counseling as it would be considered presymptomatic genetic testing.

Note: Although most individuals diagnosed with autosomal dominant ALS have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset or reduced penetrance of the disease in the affected parent.

Risk to Family Members — Autosomal Recessive ALS

At conception, each sib has a 25% chance of inheriting the homozygous pathogenic variant and being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.

Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.

Heterozygotes are asymptomatic.

Offspring of a proband. The offspring of an individual with autosomal recessive ALS are obligate heterozygotes (carriers) for a pathogenic variant.

Other family members of a proband. The sibs of obligate heterozygotes have a 50% chance of being heterozygotes.

Risk to Family Members — Empiric Risks

No data are available.

Related Genetic Counseling Issues

Testing of at-risk asymptomatic adults. Presymptomatic testing for variants associated with ALS is controversial because of incomplete penetrance, inability to predict the age of onset, and the lack of preventive measures. Because of the individualized nature of predictive testing, consultation with a genetic counselor and a psychologist to obtain informed consent is recommended. At this time, no established testing protocol (as in, e.g., Huntington disease) exists, although establishment of such protocols has been suggested [Fanos et al 2004]. However, to err on the side of caution, testing centers often follow a similar protocol.

Testing of asymptomatic individuals younger than age 18 years who are at risk for adult-onset disorders for which no treatment exists is not considered appropriate, primarily because it negates the autonomy of the child with no compelling benefit. Further, concern exists regarding the potential adverse effects that such information may have on family dynamics, the risk of discrimination and stigmatization in the future, and the anxiety that such information may cause.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Academy of Pediatrics and American College of Medical Genetics and Genomics policy statement: ethical and policy issues in genetic testing and screening of children.

Individuals younger than age 18 years who are symptomatic usually benefit from having a specific diagnosis established.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Performing prenatal testing for the pathogenic variant prior to performing genetic testing on the parent (including presymptomatic genetic testing) could reveal the parent's gene status; therefore, genetic counseling is indicated in all considerations of prenatal testing for ALS.

Requests for prenatal testing for adult-onset conditions such as ALS are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variant(s) have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or
umbrella support organizations and/or registries for the benefit of individuals
with this disorder and their families. GeneReviews is not responsible for the
information provided by other organizations. For information on selection
criteria, click here.

Data suggest that individuals under the care of such a team may have a better prognosis [van den Berg et al 2004, Andersen et al 2005]. The factors influencing survival include: age, vital capacity, fatigue, body strength, spasticity, household income, and depression [Paillisse et al 2005], most of which can be managed by the appropriate specialist in the multidisciplinary team.

Riluzole is the only currently FDA-approved drug for the treatment of ALS. Its mechanism of action is thought to be glutamate inhibition. Clinical trials have shown marginal slowing of disease progression in some but not all individuals, [Riviere et al 1998]. Riluzole is associated with elevation of serum alanine aminotransferase levels in 10% to 15% of treated individuals; in rare cases it may cause bone marrow depression [Bensimon & Doble 2004].

Oral secretions in individuals with bulbar symptoms can be reduced with tricylic antidepressants and anticholinergic agents, thus reducing the need for suctioning.

Pseudobulbar affect can be managed with antidepressants such as Nuedexta® (dextromethophan and quinidine).

Swallowing difficulties can be alleviated by thickening liquids and pureeing solid food, as well as eventually using a gastrostomy tube to help maintain caloric intake and hydration. Nutritional management, a prognostic factor for survival, has become a focus in the clinical setting.

Medications such as baclofen and benzodiazepines can help relieve spasticity and muscle cramps; however, weakness and lethargy are common side effects. Individualized moderate-intensity endurance-type exercises for the trunk and limbs may help to reduce spasticity [Ashworth et al 2004].

Low-tech (e.g., alphabet board) and high-tech (i.e., computer-assisted) devices can aid speech and communication. The recent development of the eye movement-controlled on-screen keyboard may enable communication for individuals without any remaining limb function.

Assistive devices, such as walkers or wheelchairs, can aid mobility; and others, such as bathroom installments, hospital bed, and Hoyer lift, can aid in activities of daily living at home.

Ventilatory assistance may include use of bilevel positive airway pressure (BIPAP), which has played an increasing role in preserving and prolonging quality of life in persons with ALS. In 1999, the American Academy of Neurology published norms recommending the initiation of noninvasive ventilation (NIV) in individuals with a theoretic forced vital capacity (FVC) less than 50% of predicted [Miller et al 1999]. Studies show that mean survival significantly increases when NIV is initiated prior to the onset of bulbar symptoms [Farrero et al 2005]. Therefore, evaluation by a pulmonologist should be undertaken before reduction of the forced vital capacity below 50%.

Although tracheostomy and ventilatory support can extend life span, affected individuals often decline these interventions [Albert et al 1999].

The tremendous psychological and social impact of ALS on both affected individuals and caregivers needs to be continually addressed [Goldstein et al 1998]. Hospice care, typically instituted once FVC is less than 30%, contributes to the individual’s comfort in the terminal stages.

Surveillance

Specialized multidisciplinary ALS clinic evaluations are suggested every three months.

Neurologic examination to establish the extent of weakness, atrophy, gait instability, involvement of fine motor and gross motor function and swallowing with attention to choking or coughing episodes and insensible aspiration manifesting as pneumonia

Pulmonary function tests

Nutritional status

PT/OT evaluation

Speech evaluation

Agents/Circumstances to Avoid

Patients and caregivers should be educated about safety precautions and environmental modifications for the home and at work.

Evaluation of Relatives at Risk

Therapies Under Investigation

Xaliproden slowed the rate of deterioration in FVC by 43% in individuals with ALS during Phase II safety and efficacy trials performed in France but did not improve functional or manual muscle testing scores [Lacomblez et al 2004]. Further investigations are needed.

Fornai et al [2008] reported a delay in disease progression in a small number of individuals with ALS taking a daily dose of lithium supplemental to riluzole. Additional research and clinical trials are needed to establish to neuroprotective effect of lithium.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Individuals with ALS commonly supplement their diets with vitamin E, vitamin C, B vitamins, selenium, zinc, coenzyme Q10, and herbal preparations such as ginseng, gingko biloba, and Maharishi Amrit Kalesh [Cameron & Rosenfeld 2002]. In a Cochrane Review, Orrell et al [2007] summarized and evaluated 21 clinical trials of antioxidant therapies in various combinations including: vitamin E, high-dose coenzyme Q10, vitamin C, selenium, beta-carotene, N-acetylcysteine, L-methionine, and selegiline. In the majority of these studies, the sample size was not adequate for statistical evaluation. Although the antioxidants were well tolerated in many of the trials, significant differences in longevity, muscle strength, or functional rating scales over time were not identified.

References

Published Guidelines/Consensus Statements

Committee on Bioethics, Committee on Genetics, and American College of Medical Genetics and Genomics Social, Ethical, Legal Issues Committee. Ethical and policy issues in genetic testing and screening of children. Available online. 2013. Accessed 7-1-15. [PubMed: 23428972]